Role of Lysosomal Genes for Parkinson's Pathogenesis: Insights from Molecular Mechanism to Therapeutic Strategies

Current review aims to clarify the role of lysosomal genes in the pathogenesis of Parkinson's Disease (PD), directing on the molecular mechanisms underlying lysosomal dysfunction and its involvement to α-synuclein accumulation. To deliberates PD-related genes including GBA1, LRRK2, VPS35, PRKN, PINK1, TMEM175, ATP13A2, ATP10B, and DJ1, highlighting their contribution in lysosomal damage. It investigates the disorder of lysosomal enzymes such as cathepsins, glucocerebrosidase, galactocerebrosidase, and acid sphingomyelinase, and the consequent impairment of the autophagic-lysosomal pathway, which helps pathological α-synuclein accumulation. Therapeutic approaches targeting lysosomal dysfunction and α-synuclein pathology are reviewed, including pharmacological chaperones, immunization strategies, enzyme replacement therapies, and small-molecule oligomer modulators. While recent clinical trials expose certain limitations, combinatorial treatment strategies show potential to improve therapeutic efficacy. Lysosomal pathways are critical contributors to PD pathogenesis and denote promising targets for intervention. Integrating mechanistic understandings with developing therapies underlines the importance of targeting lysosomal dysfunction to mitigate α-synuclein aggregation and advance PD treatment.